2-halo-1-hydroxy-androstane-3, 17-diones



United States Patent 3,251,835 2-HALO-1-HYDROXY-ANDROSTANE-3,17-DIONES Daniel M. Teller, King of Prussia, and Leland L. Smith, Malvern, Pa., assignors to American Home Products Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed May 1, 1m, Se'r. No. 364,299- 6 Claims. (Cl. 260239.55)

wherein X is selected from the group consisting of chlorine or bromine and Y is selected from the group consisting of and OC H O-.

The new compounds of this invention are valuable for their hormonal properties. In particularly, the claimed compounds are useful as agents for androgen therapy. When used for this purpose, they are administered in amounts and in the manner of known androgenic hormones.

The new compounds of the present invention wherein Y of Formula I is keto oxygen (=0) are prepared by reacting a A -3-ketone "with a hypohalous acid according to the following reaction:

0 0 II II US a In the foregoing sequence, X represents the substituents previously described. As will be described in greater detail hereafter, those compounds encompassed within Formula I where Y is the ethylene ketal structure 3,251,835 Patented May 17, 1966 is treated with perchloric acid followed by treatment with N-chlorosuccinimide. The reaction mixture is stirred at room temperature for a period of from 2-6 hours after which time reaction is terminated by the addition of sodium sulfite solution. Ice water is added and the resulting solids filtered and dried under vacuum. The solids are then recrystallized as desired to provide final products.

In preparing the bis-ketal product, wherein Y of (I) is OC H -O, the halogenated-hydroxy-androstane- 3,17-dione is reacted with ethylene glycol in the presence of an acid condensing agent such as p-toluenesulfonic acid and a solvent. Reflux is carried out for a period of from about 5 to about 15 hours with water being continuously removed. After completion of water removal, solvent is removed, leavinga crystallized product from which the desired product is obtained by recrystallization.

The starting androstane compound used in the process of the present invention, namely 5a-androst-l-ene-3,17- dione is available commercially.

As has been previously suggested, the new compounds of the present invention are useful as hormones. When used for hormonal therapy, the new steroids of the pres ent invention may be administered with a pharmaceutically acceptable, organic or inorganic, solid or liquid carrier suitable for enteral or parenteral administration. For making up the preparation, there can be employed substances which do not react with the new compounds, such as water, gelatine, lactose, starches, stearic acid, magnesium stearate, stearyl alcohol, talc, vegetable oils, benzyl alcohols, gums, propylene glycol, polyalkylene glycols or any otherknown carrier for medicaments. The pharmaceutical preparations may be in the solid form, for example, as capsules, tablets, dragees and the like, or in liquid form, for example, as solutions, suspensions, emulsions and the like. They may also contain auxiliary substances, such as preserving, stabilizing, wetting, emulsifying agents and the like, salts for varying the osmotic pressure, bufiers, etc.

Reference now to the examples which follow' will provide a better understanding of the new compounds of the present invention and the manner in which they are prepared.

. Example I A solution of 900 mg. of 5u-androst-1-ene-3,17-dione in 13.5 ml. of dioxane is treated with 1.35 ml. of Water, 0.14 ml. of 70% perchloric acid and finally with 480 mg. of N-chlorosuccinimide. The mixture is stirred at room temperature for three hours. Thereaction is terminated by addition of 25 ml. of 10% aqueous sodium sulfite solution. An additional 200 ml. of ice-Water is added and the solids filtered and dried in vacuum at 64 C. [for two hours. several times from methanol in order to obtain an analytical sample, free from other steroids by thin-layer chromatography [using hexane: ethyl acetate (1:1)]. The :product is ZB-chloro-la-hydroxy-5a-androstane-3;17- dione, M.P. 218222 C.; [a] +8l.2;

3.01, 5.75, 5.81 etc.

Analysis.Calcd. for 0 11 010 0, 67.34; H, 8.03;

Cl, 10.46. Found: C, 67.77; H, 7.94; C1, 1050.

Example II The solids 695 mg., are recrystallized washed with water, dried, and evaporated, and the solids.

Analysis.Calcd. for C H Bro C, 59.53; H, 7.11; Br, 20.85. Found: C, 59.60; H, 7.01; Br, 20.45.

Example III A mixture of 1.0 g. of Zfi-ChlOI'O-lcc-hYdlOXY-Saandrostane-3,17-dione, 100 mg. of p-toluenesulfonic acid, 20 -ml. of ethylene glycol, and 125 ml. of benzene is refluxed with continuous removal of water-by a Dean-Stark apparatus. After thirteen hours of reflux the mixture is washed with aqueous sodium bicarbonate solution and with water, the benzene layer is separated and dried over anhydrous magnesium sulfate, and then evaporated. The solids thereby obtained are crystallized from methanol, yielding 760 mg. of material, homogeneous on thin-layer chromatograms [hexane-ethyl acetate (1:1)]. The product 2fl-chloro-3,3; 17,17-bisethylene-dioxy-Sd-androstzinla-ol is characterized as follows: M.P. 224-226" C.; ]n

Analysis.Calcd. -for C H ClO C, 64.69; H, 8.2 6; 01, 8.35. Found: C, 64.83; H, 8.16; C], 8.25.

max.

' Example IV The invention claimed is: 1. A compound having the formula:

where X is selected from the group consisting of chlorine and bromine and Y is selected from the group consisting Of 0 and OC2H4-'O. I

2. 2/3-chloro-1a-hydroxy-5a-androstane-3,17-dione.

3. 2 8-bromo-1a-hydroxy-5a-androstane-3,17-dione.

4. 2/3-chloro-3,3; 17,17-bisethylenedioxy-5a-androstanlac-0i.

5. 2/3-bromo-3,3; 17,17-disethylenedioxy-5arandrostan- 6. The method of preparing a compound having the formula:

wherein X is selected from the group consisting of chlorine and bromine which comprises reacting 5aandrost-1-ene-3,17-dione with a hy-pohalous acid and re covering the desired product.

7 References Cited by the Examiner Loewenthal: Tetrahedron, volume 6, No. 4, :pages 269- 303 (1959),.pages 287-289 relied on.

LEWIS GOTTS, Primary Examiner. HENRYA. FRENCH, Assistant Examiner. 

1. A COMPOUND HAVING THE FORMULA: 